Hemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells

Hematopoiesis occurs in distinct waves. “Definitive” hematopoietic stem cells (HSCs) with the potential for all blood lineages emerge in the aorta-gonado-mesonephros, while “primitive” progenitors, whose potential is thought to be limited to erythrocytes, megakaryocytes, and macrophages, arise earlier in the yolk sac (YS). Here, we questioned whether other YS lineages exist that have not been identified, partially owing to limitations of current lineage tracing models. We established the use of Cdh5-CreERT2 for hematopoietic fate mapping, which revealed the YS origin of mast cells (MCs). YS-derived MCs were replaced by definitive MCs, which maintained themselves independently from the bone marrow in the adult. Replacement occurred with tissue-specific kinetics. MCs in the embryonic skin, but not other organs, remained largely YS derived prenatally and were phenotypically and transcriptomically distinct from definite adult MCs. We conclude that within myeloid lineages, dual hematopoietic origin is shared between macrophages and MCs. Gentek et al. demonstrate that Cdh5-CreERT2 can be used to selectively fate map yolk sac and definitive hematopoiesis. Temporally defined Cdh5-CreERT2 lineage tracing reveals that mast cells are yolk sac derived in the embryo but replaced by definitive hematopoiesis in the adult, a feature they share with macrophages.